Melanocyte Stimulating Hormone (MSH, also called as melanotropin) produced by processing of proopiomelanocortin (POMC), a hypothalamic hormone, is known to be involved in skin pigmentation, inflammation, immunity, modulation of food intake and the like, and to affect memory and learning, regulation of body temperature, pain transmission, sexual behavior, affective behavior and the like. MSH has three types (α, β and γ) and they express a variety of physiological functions by mediation of melanocortin receptor (MC-R), which is a G protein-coupled receptor (GPCR). Five subtypes of melanocortin receptor (MC-1R, 2R, 3R, 4R and 5R) have been identified, and these are expressed in different tissues. MC-1R is mainly expressed in melanocytes, affecting skin or hair color of animal by leading to synthesis of eumelanin from phaeomelanin through control of tyrosinase. MC-2R is expressed in the adrenal gland and represents the adrenocorticotropic hormone (ACTH) receptor. MC-3R is expressed in the brain, gut, and placenta and involved in the control of food intake and thermogenesis. MC-4R is expressed in the brain, and modulates feeding behavior. MC-5R is expressed unusually in many tissues, including placenta, lung, adrenal gland, brain, white fat tissue, exocrine glands, and the like. MC-5R knockout mice have been reported to have reduced sebaceous gland lipid production, though physiological activities mediated by MC-5R are not clearly known (Cell, Vol. 91, page 789, 1997).
The MSH-melanocortin receptor system is well known to be involved in regulation of immunity, and α-MSH is reported to antagonize the action of IL-1α, IL-6, TNF-α and the like, which are inflammatory cytokines, and also to induce the production IL-10, which is an anti-inflammatory cytokine (Trends in Endocrinology and Metabolism (TEM), Vol. 11, page 304, 2000).
In recent years, it has been confirmed that melanocortin system is involved in sexual function and sexual behavior. Cyclic heptapeptide (MT-II (Melanotan-II)), a melanocortin receptor nonselective agonist has been recognized to cause erection by subcutaneous administration to male adults suffering from psychogenic erectile dysfunction (Journal of Urology (J. Urol.), Vol. 160, page 389, 1998). Furthermore, it has been reported that α-MSH administered intracerebroventricularly to male rats, causes erection, and this action is partially suppressed by administration of HS014, a selective peptide antagonist of melanocortin type 4 receptor (MC-4R) (European Journal of Pharmacology (Eur. J. Pharmacol.), Vol. 362, page 95, 1998).
It has also been confirmed that the melanocortin system, particularly, MC-4R, exerts important actions downstream of leptin in modulating food intake. Feeding behavior is an indispensable action for life maintenance in a number of living creatures including human, and abnormality of feeding behavior may result in the failure of normal life functions, and may lead to disease in many cases. In recent years, the rapid increase of obesity due to life-style changes has been recognized as a social problem. It is well known that obesity is an important risk factor for life style diseases, such as diabetes mellitus, hypertension and arteriosclerosis, and increased body weight may result in excessive burdens on the joints, such as the knee, thus causing arthritis and/or pain. In addition, the potential population who desires to lose weight is large, as suggested by the diet boom and the like, and there have been reported many cases of feeding disorders, such as bulimia and anorexia, that are caused from genetic or mental factors, such as stress. Therefore, a drug for regulating food intake is highly demanded, and research into developing an agent for preventing or treating obesity or an agent for suppressing food intake has been underway for some time.
On the other hand, many feeding regulation factors represented by leptin, have been identified. As a feeding-increasing factor acting on hypothalamus, melanin-concentrating hormone (MCH) and orexin have recently been reported in addition to neuropeptide Y (NPY). As a feeding suppressing factor, cholecystokinin (CCK) and corticotrophin-releasing hormone (CRH) and the like are known as well as the above-described α-melanocyte-stimulating hormone (α-MSH).
Reports that demonstrate the involvement of melanocortin system in feeding behavior or obesity include the following:
1) Ay mice and KKAY mice in which Agouti Protein, an agonist of the MC-1R, MC-3R and-4R, is overexpressed, are used as an animal model for obesity, indicating that blocking the action of MC-1R, MC-3R and-4R by Agouti Protein can lead to hyperphagia and obesity;
2) MC-4R knockout mice exhibit a similar phenotype to Ay mice and KKAy mice, and can lead to severe hyperphagia, obesity, insulin-resistant diabetes (Cell, Vol. 88, page 131, 1997);
3) MT-II, a non-selective MC-R agonist injected intracerebroventricularly in feeding-increased animal models (ob/ob mice, Ay mice, KKAy mice, rats or mice which are fast, or feeding-increased by administration of NPY) suppresses food intake. Furthermore, if SHU-9119 (MC-3R and 4R antagonist; MC-1R and MC-5R agonist) is injected intracerebroventricularly at the same time, the food intake suppressing activity of MT-II disappears and hyperphagia is again induced; and
4) Chronic intraperitoneal treatment of Zucker fatty rats with HP228, an α-NDP-MSH (α-[Nle4,D-Phe7] MSH) derivative, has been reported to activate melanocortin receptor to attenuate food intake and body weight gain over a 12-week period.
Therefore, developments are ongoing for an antiobestic drug or feeding control drug on the basis of the new feeding-suppressing action to control the action of these feeding control factors. Presently, central appetite suppressants, such as mazindol and sibutramine are on the market. However, due to their mechanism of action, which involves inhibiting the reuptake of cerebral amines such as adrenaline and serotonin, these drugs have side effects on the cardiovascular system and the like, and may cause habituation and dependence, and are thus not sufficient to completely address the disorders.
In conclusion from the above, a drug acting on melanocortin receptors, particularly MC-R agonist, is expected to act an anti-inflammatory drug, a sexual function-improving drug, an appetite suppressant, an anti-obesity drug, and the like. MC-R antagonists are also expected to act as therapeutic drugs for anorexia and other diseases due to the increase in melanocortin system, and are also expected to be used for elucidating the physiological actions of melanocortin system.
As a substance acting on melanocortin receptor, numerous lot of peptide compounds have been reported, including MT-II, HS014, SHU-9119, Q-NDP-MSH and HP228, which are the above-described α-MSH-related peptides, as well as HS024, HS028, Ro 27-3225, Ro 27-4680 and the like. On the other hand, low molecular weight compounds, such as spiropiperidine derivatives (International Publication Nos. WO 99/64002 and WO 01/70337) and piperidine derivatives (International Publication No. WO 01/70708) are known as MC-R agonists, piperidine derivatives (International Publication No. WO 00/74679) as MC-4R agonist, and aromatic amines and amide derivatives (International Publication Nos. WO 01/55106, WO 01/55107, and WO 01/55109) as substances acting on MC-R.
On the other hand, biaryl compounds are disclosed. For example, Japanese Unexamined Patent Application Publication No. 6-107649 discloses a biphenyl compound having 5-HT (serotonin) receptor antagonistic activity and 4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboamide hydrochloride in Example 10. Japanese Unexamined Patent Application Publication No. 10-510512 (International Publication No. WO 96/10559) discloses a compound represented by the formula:

wherein R4 is dialkylamino, phenyl optionally having protected amino and the like and the like; Y is a bond and the like, R2 is lower alkyl and the like; R3 is aryl optionally having one or more appropriate substituents and the like; and n is 0 or 1; or a salt thereof, is useful as ACAT inhibitor. However, there has been no report that a biaryl compound including these compounds acts on MC-R.
The present invention provides a novel biaryl compound or a salt thereof having the action of agonist or antagonist on melanocortin receptor (MC-R), and a drug useful as an agent for preventing or treating inflammatory diseases, such as rheumatism or sepsis, AIDS, obesity, bulimia or anorexia, or as an agent for improving sexual dysfunction or affective disorders, based on MC-R agonist /antagonist action.